Many neurons synthesize and secrete small peptides that act on specific postsynaptic receptors and modify the activity of target neurons. Specific receptor molecules have been identified by binding studies and in some cases, such as the neurokinin-1 receptor (NK-1R) for Substance P (SP), the receptor has been cloned and sequenced. The NK-1R is found in many locations thought to be postsynaptic to SP-secreting terminals such as the cortical nucleus of the amygdala, striatum, locus coeruleus, rostral half of the nucleus ambiguous, nucleus tractus solitarius, dorsal motor nucleus of the vagus, intermediolateral cell column and lamina I and III of the dorsal horn of the spinal cord (1,2). Studies with agonists and antagonists indicate that most, if not all, of the effects of SP in the mammalian CNS are attributable to action at the G-protein coupled NK-1R (3).
A number of functional roles have been attributed to SP in keeping with anatomical studies (e.g. (3)) that show neurons expressing SP in a number of locations throughout the CNS, PNS and gut. For example, experiments utilizing injections of SP into the lateral ventricles have shown increases in blood pressure and heart rate as well as stereotyped behaviors such as face washing, grooming, and wet dog shakes (3). These autonomic manifestations are likely attributable to action in the medulla where prominent NK-1R expression has been demonstrated in the nucleus tractus solitarius, and stereotyped behaviors may reflect action in the basal ganglia and/or limbic system (1,4-6). The current state of knowledge, however, does not unambiguously identify the site of action for these and many other effects of SP. All of these actions are likely mediated through action of substance P at NK-1R (3,4).
The best known role for SP is in nociception. Small unmyelinated C-fibers of the peripheral nervous system that are thought to be primary nociceptive neurons secrete SP and glutamate. Capsaicin, an agent that can destroy C-fibers, produces cutaneous analgesia and is approved for topical use to alleviate the pain of postherpetic neuralgia (Zostrix). Capsaicin injection of neonates has long been used to produce animals with no C-fibers and altered threshold to painful cutaneous stimuli. SP-containing nerve terminals are present in the spinal nucleus of the trigeminal nerve and the superficial layers of the spinal dorsal horn, areas known to be important in pain perception (1) and rich in NK-1R (1,2). In spite of the development of peptide and nonpeptide antagonists of NK-1R, considerable controversy remains about the precise role of SP acting at NK-1R in pain perception (7-17).